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Josefine Bostner Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Elin Karlsson Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Cecilia Bivik Eding Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Gizeh Perez-Tenorio Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Hanna Franzén Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Aelita Konstantinell Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Tommy Fornander Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Bo Nordenskjöld Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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Olle Stål Department of Clinical and Experimental Medicine, Department of Clinical and Experimental Medicine, Department of Oncology, Department of Oncology

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/mammalian target of rapamycin (PI3K/mTOR) cascade is a characterized mechanism of endocrine resistance, with aberrant stimulation promoting estrogen receptor (ER) α (ESR1) activation and tumor growth, despite estrogen antagonizing- or estrogen restriction

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Yuet-Kin Leung Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Hung-Ming Lam Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Shulin Wu Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Dan Song Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Linda Levin Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Liang Cheng Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Chin-Lee Wu Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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Shuk-Mei Ho Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health
Division of Environmental Genetics and Molecular Toxicology, Division of Epidemiology and Biostatistics, Center for Environmental Genetics, Cancer Center, Department of Pathology, Department of Pathology and Laboratory Medicine, Department of Environmental Health

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. 1988 ), a thesis supported by animal studies ( Prins 1997 , Ho et al . 2006 , Prins & Korach 2008 ). Estrogen receptors (ER), ERα and ERβ, are the major mediators of estrogen signaling. Upon binding of estradiol-17β, ER in the nucleus forms a homo

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Frances Collins The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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Nozomi Itani The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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Arantza Esnal-Zufiaurre The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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Douglas A Gibson The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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Carol Fitzgerald The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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Philippa T K Saunders The University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK

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) Chakraborty S Willett H Biswas PK 2012 Insight into estrogen receptor beta-beta and alpha-beta homo- and heterodimerization: a combined molecular dynamics and sequence analysis study . Biophysical Chemistry 42 – 50 . ( https://doi.org/10.1016/j

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Ville Paakinaho Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

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Jorma J Palvimo Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

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cancers whose development and growth are initially steroid hormone-dependent ( Metcalfe et al. 2018 , Dhiman et al. 2018 ). The family of SRs consists of estrogen receptor (ER), and 3-ketosteroid receptors (NR3Cs), glucocorticoid (GR, NR3C1

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Yong-Zi Chen Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China

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Youngchul Kim Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

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Hatem H Soliman Department of Women’s Oncology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Department of Clinical Sciences, College of Medicine, University of South Florida, Tampa, Florida, USA

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GuoGuang Ying Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China

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Jae K Lee Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Department of Clinical Sciences, College of Medicine, University of South Florida, Tampa, Florida, USA

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ER-negative breast cancer includes most aggressive subtypes of breast cancer such as triple negative (TN) breast cancer. Excluded from hormonal and targeted therapies effectively used for other subtypes of breast cancer, standard chemotherapy is one of the primary treatment options for these patients. However, as ER− patients have shown highly heterogeneous responses to different chemotherapies, it has been difficult to select most beneficial chemotherapy treatments for them. In this study, we have simultaneously developed single drug biomarker models for four standard chemotherapy agents: paclitaxel (T), 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) to predict responses and survival of ER− breast cancer patients treated with combination chemotherapies. We then flexibly combined these individual drug biomarkers for predicting patient outcomes of two independent cohorts of ER− breast cancer patients who were treated with different drug combinations of neoadjuvant chemotherapy. These individual and combined drug biomarker models significantly predicted chemotherapy response for 197 ER− patients in the Hatzis cohort (AUC = 0.637, P = 0.002) and 69 ER− patients in the Hess cohort (AUC = 0.635, P = 0.056). The prediction was also significant for the TN subgroup of both cohorts (AUC = 0.60, 0.72, P = 0.043, 0.009). In survival analysis, our predicted responder patients showed significantly improved survival with a >17 months longer median PFS than the predicted non-responder patients for both ER− and TN subgroups (log-rank test P-value = 0.018 and 0.044). This flexible prediction capability based on single drug biomarkers may allow us to even select new drug combinations most beneficial to individual patients with ER− breast cancer.

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Sung Gwe Ahn Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Chang Ik Yoon Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Jae Hoon Lee Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Hye Sun Lee Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea

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So Eun Park Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Yoon Jin Cha Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Chihwan Cha Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Soong June Bae Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Kyung-A Lee Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Joon Jeong Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Background In estrogen receptor (ER)-positive breast cancer, progesterone receptor (PR) expression is generally considered a marker of an intact estrogen-responsive pathway ( Horwitz & McGuire 1975 ). In addition, patients with ER

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Hyun Ho Han Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea

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Baek Gil Kim Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea

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Joo Hyun Lee Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

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Suki Kang Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea

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Ji Eun Kim Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

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Nam Hoon Cho Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, South Korea
Global 5-5-10 System Biology, Yonsei University, Seoul, South Korea

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et al . 2005 , Janni et al . 2011 ). Recurrence after long period of dormancy is especially common in estrogen receptor-positive (ER+) breast cancer ( Han et al . 2016 , Zhang et al . 2013 ). While estrogen receptor-negative (ER−) cancer rarely

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Pratima Basak Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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Sumanta Chatterjee Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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Steven Weger Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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M Christine Bruce Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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Leigh C Murphy Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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Afshin Raouf Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5

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Introduction Estrogen signaling through estrogen receptor α (ERα) is pivotal to the survival and maintenance of ERα + breast cancer tumors. Furthermore, the estrogen–ERα signaling axis has been shown to be indispensable to mammary gland development

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Per Eystein Lønning Section of Oncology, Department of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway
Section of Oncology, Department of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

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Hans Petter Eikesdal Section of Oncology, Department of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway
Section of Oncology, Department of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

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( Lønning et al . 1990 ). Thus, aromatization of androstenedione into E 1 is the major pathway of estrogen synthesis in postmenopausal women. While E 1 is inactive by itself with respect to stimulating estrogen receptor activation, it is easily converted

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Haojun Luo
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Guanglun Yang Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Tenghua Yu Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Shujuan Luo Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Chengyi Wu Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Yan Sun Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Manran Liu Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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Gang Tu Department of Breast and Thyroid Surgery, Department of Endocrine and Breast Surgery, Department of Gynecology and Obstetrics, Key Laboratory of Laboratory Medical Diagnostics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

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are recognized as co-mediators of tumor progression rather than as merely bystanders. Estrogen is well recognized as a mitogen for breast cancer cells. Traditionally, estrogenic effects have been ascribed to the nuclear estrogen receptors (ERα and ERβ

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